記述言語：日本語   出版者・発行元：日本医科大学医学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J04260&link_issn=&doc_id=20240909190019&doc_link_id=10.1272%2Fmanms.20.214&url=https%3A%2F%2Fdoi.org%2F10.1272%2Fmanms.20.214&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Osimertinib is a standard treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and is highly effective for brain metastases (BMs). However, it is unclear whether local treatment (LT) for BMs prior to osimertinib administration improves survival in EGFR-mutant NSCLC. We aimed to reveal the survival benefit of upfront local treatment (LT) for BMs in patients treated with osimertinib. MATERIALS AND METHODS: This multicenter retrospective study included consecutive patients with EGFR mutation (19del or L858R)-positive NSCLC who had BMs before osimertinib initiation between August 2018 and October 2021. We compared overall survival (OS) and central nervous system progression-free survival (CNS-PFS) between patients who received upfront LT for BMs (the upfront LT group), and patients who received osimertinib only (the osimertinib-alone group). Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for potential confounding factors. RESULTS: Of the 121 patients analyzed, 57 and 64 patients had 19del and L858R, respectively. Forty-five and 76 patients were included in the upfront LT group and the osimertinib-alone groups, respectively. IPTW-adjusted Kaplan-Meier curves showed that the OS of the upfront LT group was significantly longer than that of the osimertinib-alone group (median, 95 % confidence intervals [95 %CI]: Not reached [NR], NR-NR vs. 31.2, 21.7-33.2; p = 0.021). The hazard ratio (HR) for OS and CNS-PFS was 0.37 (95 %CI, 0.16-0.87) and 0.36 (95 %CI, 0.15-0.87), respectively. CONCLUSIONS: The OS and CNS-PFS of patients who received upfront LT for BMs followed by osimertinib were significantly longer than those of patients who received osimertinib alone. Upfront LT for BMs may be beneficial in patients with EGFR-mutant NSCLC treated with osimertinib.

DOI： 10.1016/j.lungcan.2024.107540

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Small cell lung cancer (SCLC) is well known as a highly malignant neuroendocrine tumor. Immunotherapy combined with chemotherapy has become a standard treatment for extensive SCLC. However, since most patients quickly develop resistance and relapse, finding new therapeutic targets for SCLC is important. We obtained four microarray datasets from the Gene Expression Omnibus database and screened differentially expressed genes by two methods: batch correction and "RobustRankAggregation". After the establishment of a protein-protein interaction network through Cytoscape, seven hub genes (AURKB, BIRC5, TOP2A, TYMS, PCNA, UBE2C, and AURKA) with high expression in SCLC samples were obtained by eight CytoHubba algorithms. The Least Absolute Shrinkage and Selection Operator regression and the Wilcoxon test were used to analyze the differences in the immune cells' infiltration between normal and SCLC samples. The contents of seven kinds of immune cells were considered to differ significantly between SCLC samples and normal samples. A negative association was found between BIRC5 and monocytes in the correlation analysis between immune cells and the seven hub genes. The subsequent in vitro validation of experimental results showed that downregulating the expression of BIRC5 by siRNA can promote apoptotic activity of SCLC cells and inhibit their vitality, migration, and invasion. The use of BIRC5 inhibitor inhibited the vitality of SCLC cells and increased their apoptotic activity. BIRC5 may be a novel therapeutic target option for SCLC.

DOI： 10.1038/s41598-024-58454-4

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Everolimus, a mammalian target of rapamycin inhibitor used as an antineoplastic drug, is associated with a remarkably high incidence of interstitial lung disease (ILD). The clinical and pathological characteristics of ILD caused by everolimus have not been thoroughly investigated; therefore, we aimed to elucidate the features of everolimus-associated ILD. METHODS: We retrospectively reviewed the medical records of patients who received everolimus for cancer treatment at our hospital. Patient backgrounds were compared between the ILD and non-ILD groups. Chest computed tomography (CT), changes in biomarkers, and lung histopathological features were analyzed for ILD cases. RESULTS: Sixty-six patients were reviewed, and ILD developed in 19. There were no differences in patient demographics between the ILD and non-ILD groups. The severity of ILD was grade 1 (G1) in 9 and grade 2 (G2) in 10 cases. Chest CT showed organizing pneumonia (OP) or a hypersensitive pneumonia pattern. The levels of lactate dehydrogenase, C-reactive protein, Krebs von den lungen-6, and surfactant protein-D (SP-D) at the onset of ILD were significantly higher than those at baseline. Analysis of G1 and G2 ILD subgroups showed a higher SP-D levels in the G2 subgroup. Five patients underwent lung biopsies; all specimens demonstrated alveolitis with lymphocytic infiltration and granulomatous lesions, and some had OP findings. CONCLUSIONS: Everolimus-associated ILD is mild and has a favorable prognosis. Patients with symptomatic ILD were more likely to have higher SP-D levels than those with asymptomatic ILD. Granulomatous lesions are an important pathological feature of everolimus-associated ILD.

DOI： 10.1272/jnms.JNMS.2024_91-211

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Immune check point inhibitors (ICIs) have durable antitumor effects. However, autoimmune toxicities, termed immune-related adverse events, occur in some patients. We report a case of severe immune aplastic anemia (AA) in a patient with non-small cell lung cancer who was receiving atezolizumab with bevacizumab/carboplatin/paclitaxel. Although the cancer has not recurred, his bone marrow is depleted and he did not respond to immunosuppressive therapy. He has survived for 1.5 years with blood transfusions and infection control. Immune AA associated with ICIs is rare, and a treatment has not yet been established. This case report provides information on the management and treatment response of patients with AA caused by ICIs. Further studies should investigate the mechanism and pathogenesis of immune AA caused by ICIs.

DOI： 10.1272/jnms.JNMS.2024_91-302

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 69-year-old woman was diagnosed with idiopathic interstitial pneumonia (IIP). The patient underwent a combination therapy of steroid therapy and intravenous cyclophosphamide, long-term oxygen therapy, and the initiation of Nintedanib. However, there was no improvement in IIP, and as a result, the activities of daily living also declined. As one of the various examinations conducted, the results of the right heart catheterization diagnosed the patient with mild pulmonary hypertension, and Macitentan therapy was initiated. The subsequent clinical course appeared to show an improvement in Idiopathic Interstitial Pneumonia (IIP) by adding Macitentan therapy to Nintedanib therapy.

DOI： 10.1016/j.rmcr.2024.102058

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, is crucial in treating hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic or recurrent breast cancer. However, its association with drug-induced interstitial lung disease (DI-ILD) is concerning. We present an 82-year-old woman with breast cancer receiving abemaciclib, who developed persistent cough and malaise. Initial diagnostics suggested pneumonia, supported by ground-glass opacities and consolidations on chest high-resolution computed tomography. Suspecting DI-ILD, a transbronchial lung cryobiopsy (TBLC) was performed, revealing fibrosing organizing pneumonia and confirming abemaciclib-induced ILD. Discontinuing abemaciclib led to significant symptom improvement, supporting the diagnosis. This case report describes the clinical presentation and diagnostic approach in a patient with suspected abemaciclib-induced ILD, including the use. To our knowledge, this is the first reported case of fibrosing organizing pneumonia as a histopathological pattern in abemaciclib-induced ILD, expanding knowledge of this therapy's pulmonary adverse events. Histopathological features included diffuse lymphocytic infiltration, polypoid intra-alveolar fibrosis, intraluminal granulation tissue plugs with dense hyalinization, hyalinized fibrotic alveolar septa lesions, and obliterative fibrotic processes affecting alveolar ducts. Our case suggests that TBLC might be useful in recognizing DI-ILD by providing detailed lung tissue examination, which can facilitate early diagnosis and guide management. Identifying fibrosing organizing pneumonia indicated a potentially corticosteroid-responsive pathology, suggesting a more favorable prognosis compared with patterns like diffuse alveolar damage. This case highlights the potential for abemaciclib-induced ILD to occur even after prolonged treatment periods, emphasizing the importance of vigilance and consideration of diagnostic intervention for patients on cyclin-dependent kinase 4/6 inhibitors presenting with respiratory symptoms. Timely recognition and appropriate management may mitigate adverse outcomes. Further studies are needed to confirm these findings and to better understand the role of TBLC and histopathological examination in diagnosing and managing abemaciclib-induced ILD.

DOI： 10.1177/11782234241301314

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A female patient developed multiple intestinal perforations at 31 and 43 years of age. Because of her family history of pneumothorax and intestinal perforation, Ehlers-Danlos syndrome (EDS) was suspected when she visited our hospital at 52 years. She was diagnosed with vascular Ehlers-Danlos syndrome (vEDS) and developed bilateral external iliac artery dissection. A CT scan at the time of admission revealed granular and infiltrative shadows in both lungs with bronchiectasis. The patient was also diagnosed with Mycobacterium avium complex (MAC) pulmonary disease, and drug susceptibility to clarithromycin was confirmed. After treatments with rifampicin, ethambutol, and clarithromycin were started, the acid-fast bacilli cultures taken from sputum were negative, and respiratory symptoms partially improved after about 1 month. vEDS is reportedly associated with lung diseases, such as pneumothorax and cystic lung lesions, but there are few reports of respiratory infections with vEDS. Moreover, there are no reports of complications associated with MAC disease. We report a case of vEDS with rare complications and suggest the possible mechanism of infection.

DOI： 10.1016/j.rmcr.2024.102119

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The mechanisms of fibrosis onset and development remain to be elucidated. However, it has been reported that mechanical stretch promotes fibrosis in various organs and cells, and may be involved in the pathogenesis of pulmonary fibrosis. We demonstrated that ventilator-induced lung hyperextension stimulation in mice increased the expression of connective tissue growth factor (CTGF), a profibrotic cytokine, in lung tissue. Increased CTGF expression induced by cyclic mechanical stretch (CMS) was also observed in vitro using A549 human alveolar epithelial cells. Pathway analysis revealed that the induction of CTGF expression by CMS involved MEK phosphorylation. Furthermore, early growth response 1 (Egr-1) was identified as a transcription factor associated with CTGF expression. Finally, the antifibrotic drug pirfenidone significantly reduced CTGF expression, MEK phosphorylation, and Egr-1 levels induced by CMS. Thus, our results demonstrated that profibrotic cytokine CTGF induced by CMS may be a therapeutic target of pirfenidone.

DOI： 10.1016/j.resp.2023.104142

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: TAS-115, a novel oral multi-kinase inhibitor, showed antifibrotic effects in in vitro and in vivo animal models of idiopathic pulmonary fibrosis (IPF). METHODS: In this exploratory phase 2 study, IPF patients with a percent predicted forced vital capacity (%FVC) decline ≥5% acquired within the previous 6 months were enrolled. Patients were divided into three pre-treatment cohorts, namely, treatment-naïve, pirfenidone, or nintedanib. TAS-115 was administered orally at 200 mg/day with a 5-day on and 2-day off regimen. After 13 weeks of treatment, patients entered a 13-week extension treatment period where the efficacy was evaluated. The primary endpoint was the difference in slope of %FVC decline at Week 13 from baseline. Safety was also evaluated. RESULTS: Between June 2018 and July 2019, 46 patients were enrolled, and 30 (65.2%) patients completed the 13-week treatment. Of these, 22 (47.8%) proceeded to extension treatment. For the primary endpoint, TAS-115 treatment lowered the slope of the %FVC decline of 0.0750%/day (95% confidence interval: 0.0341-0.1158%/day) at Week 13. Efficacy was also demonstrated at Week 26. Treatment-related adverse events were reported in 40 (88.9%) patients, but most were manageable by dose reduction, dose interruption, or symptomatic treatment. CONCLUSIONS: TAS-115 treatment was effective, assessed using intra-patient change in slope of %FVC decline as a surrogate endpoint in patients with IPF pre-treated with pirfenidone or nintedanib and treatment-naïve patients. TAS-115 showed acceptable tolerability and a manageable safety profile. TRIAL REGISTRATION: Japic-Clinical Trials Information, JapicCTI-183898 (first registered: March 15, 2018).

DOI： 10.1016/j.resinv.2023.04.008

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sarcoidosis is a multisystem disease with an unknown etiology and is characterized by the formation of noncaseating granulomas in the affected organs. We present the case of a 69-year-old male Japanese patient with bilateral hilar lymphadenopathy on chest radiographs for more than 10 years, left without further investigation. The patient reported no clinical symptoms. Chest computed tomography revealed ground-glass opacities and reticular shadows in both lungs, along with bilateral hilar and mediastinal lymphadenopathy. Lymphocytosis was observed in bronchoalveolar lavage fluid. Pathological examination of transbronchial lung biopsy revealed noncaseating, epithelioid granulomas congruous with sarcoidosis, together with other findings. There were no abnormalities on electrocardiogram, echocardiogram, and ophthalmic examination.For progressive dyspnea on exertion, systemic corticosteroid therapy with oral prednisolone (25 mg/day) was initiated in 2017 and gradually tapered. Despite this intervention, the decline in forced vital capacity (FVC) was accelerated. Three years later, the patient noticed swelling in his right wrist. Further investigation revealed elevated anti-cyclic citrullinated peptide antibodies and absence of noncaseating epithelioid granuloma on surgical biopsy, leading to the diagnosis of rheumatoid arthritis (RA). Thereafter, the anti-fibrotic agent nintedanib was initiated, because interstitial lung disease (ILD) was considered to have converted into a progressive fibrosing phenotype (PF-ILD) with overlapping RA-associated lung involvement. With treatment, the progression of decline in FVC was slowed, although home oxygen therapy was introduced.

DOI： 10.1177/17534666231158279

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：日本サルコイドーシス  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Idiopathic pulmonary fibrosis (IPF), a progressive disorder of unknown etiology, is characterized by pathological lung fibroblast activation and proliferation resulting in abnormal deposition of extracellular matrix proteins within the lung parenchyma. The pathophysiological roles of exosomal microRNAs in pulmonary fibrosis remain unclear; therefore, we aimed to identify and characterize fibrosis-responsive exosomal microRNAs. We used microRNA array analysis and profiled the expression of exosome-derived miRNA in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. The effect of microRNAs potentially involved in fibrosis was then evaluated in vivo and in vitro. The expression of exosomal microRNA-16 was increased by up to 8.0-fold on day 14 in bleomycin-treated mice, compared to vehicle-treated mice. MicroRNA-16 mimic administration on day 14 after bleomycin challenge ameliorated pulmonary fibrosis and suppressed lung and serum expression of secreted protein acidic and rich in cysteine (SPARC). Pretreatment of human lung fibroblasts with the microRNA-16 mimic decreased the expression of rapamycin-insensitive companion of mTOR (Rictor) and TGF-β1-induced expression of SPARC. This is the first study reporting the anti-fibrotic properties of microRNA-16 and demonstrating that these effects occur via the mTORC2 pathway. These findings support that microRNA-16 may be a promising therapeutic target for IPF.

DOI： 10.1016/j.yexcr.2020.112416

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Measuring lung compliance is useful for evaluating interstitial lung disease (ILD) progression because reduced lung compliance by fibrosis progression is the main primary cause of decreased vital capacity. However, because of the invasiveness of the method, requiring the insertion of a balloon into the esophagus, lung compliance is rarely measured. A recently developed, possible method estimates intrathoracic pressure using fingertip photoplethysmography. This method non-invasively measures the lung dynamic compliance (Cdyn) by simultaneously measuring tidal volume. We evaluated the efficacy of this method in assessing ILD. METHODS: We conducted a single-center, observational cross-sectional study to evaluate the efficacy of this method in subjects with ILD as compared with that in healthy control subjects. The main outcome was the estimated Cdyn (eCdyn) determined using this method. We also evaluated potential confounding factors of eCdyn in the baseline characteristics. RESULTS: In the ILD group (n = 14) the median eCdyn was significantly lower than that in the control group (n = 49) (0.122 vs. 0.183; P = 0.011). In univariate regression analysis, eCdyn was significantly correlated with height, weight, forced vital capacity, forced expiratory volume in one second, diffusing capacity for carbon monoxide, and usual interstitial pneumonia (UIP). In multivariate regression analysis, both weight (β = 0.49, P = 0.011) and UIP (β = 0.52, P = 0.007) were significantly associated with eCdyn. CONCLUSIONS: We demonstrated a significant reduction in Cdyn in subjects with ILD using photoplethysmography. This non-invasive method might be a novel, promising tool for evaluating fibrosis progression in ILD.

DOI： 10.1272/jnms.JNMS.2021_88-411

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1272/jnms.JNMS.2020_87-302

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記述言語：英語  

DOI： 10.1016/j.resinv.2018.07.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality, and the pathogenesis of the disease is still incompletely understood. Although lymphocytes, especially CD4+CD25+FoxP3+ regulatory T cells (Tregs), have been implicated in the development of IPF, contradictory results have been reported regarding the contribution of Tregs to fibrosis both in animals and humans. The aim of this study was to investigate whether a specific T cell subset has therapeutic potential in inhibiting bleomycin (BLM)-induced murine pulmonary fibrosis. METHODS: C57BL/6 mice received BLM (100 mg/kg body weight) with osmotic pumps (day 0), and pulmonary fibrosis was induced. Then, splenocytes or Tregs were adoptively transferred via the tail vein. The lungs were removed and subjected to histological and biochemical examinations to study the effects of these cells on pulmonary fibrosis, and blood samples were collected by cardiac punctures to measure relevant cytokines by enzyme-linked immunosorbent assay. Tregs isolated from an interleukin (IL)-10 knock-out mice were used to assess the effect of this mediator. To determine the roles of the spleen in this model, spleen vessels were carefully cauterized and the spleen was removed either on day 0 or 14 after BLM challenge. RESULTS: Splenocytes significantly ameliorated BLM-induced pulmonary fibrosis when they were administered on day 14. This effect was abrogated by depleting Tregs with an anti-CD25 monoclonal antibody. Adoptive transfer of Tregs on day 14 after a BLM challenge significantly attenuated pulmonary fibrosis, and this was accompanied by decreased production of fibroblast growth factor (FGF) 9-positive cells bearing the morphology of alveolar epithelial cells. In addition, BLM-induced plasma IL-10 expression reverted to basal levels after adoptive transfer of Tregs. Moreover, BLM-induced fibrocyte chemoattractant chemokine (CC motif) ligand-2 production was significantly ameliorated by Treg adoptive transfer in lung homogenates, accompanied by reduced accumulation of bone-marrow derived fibrocytes. Genetic ablation of IL-10 abrogated the ameliorating effect of Tregs on pulmonary fibrosis. Finally, splenectomy on day 0 after a BLM challenge significantly ameliorated lung fibrosis, whereas splenectomy on day 14 had no effect. CONCLUSIONS: These findings warrant further investigations to develop a cell-based therapy using Tregs for treating IPF.

DOI： 10.1186/s12931-018-0783-2

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記述言語：英語  

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality, and the pathogenesis of the disease is still incompletely understood. Although lymphocytes, especially CD4CD25FoxP3 regulatory T cells (Tregs), have been implicated in the development of IPF, contradictory results have been reported regarding the contribution of Tregs to fibrosis both in animals and humans. The aim of this study was to investigate whether a specific T cell subset has therapeutic potential in inhibiting bleomycin (BLM)-induced murine pulmonary fibrosis.C57BL/6 mice received BLM (100 mg/kg body weight) with osmotic pumps (day 0), and pulmonary fibrosis was induced. Then, splenocytes or Tregs were adoptively transferred via the tail vein. The lungs were removed and subjected to histological and biochemical examinations to study the effects of these cells on pulmonary fibrosis, and blood samples were collected by cardiac punctures to measure relevant cytokines by enzyme-linked immunosorbent assay. Tregs isolated from an interleukin (IL)-10 knock-out mice were used to assess the effect of this mediator. To determine the roles of the spleen in this model, spleen vessels were carefully caut

DOI： 10.1186/s12931-018-0783-2

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記述言語：英語  

Objectives Acute exacerbation of idiopathic pulmonary fibrosis (IPF-AE) has been recognized as a fatal pulmonary disorder, but the exact prognostic factors are unknown. The aim of the present study was to analyze the clinical characteristics of patients with IPF-AE and identify the prognostic factors. Methods The medical records of 59 cases of IPF-AE were retrospectively reviewed. Clinical data, laboratory data, radiographic findings, treatment, and time from the onset of symptoms to the initiation of corticosteroid pulse therapy, i.e. symptom duration, and outcome were analyzed. Results The IPF Stage, Gender-Age-Physiology (GAP) Index, symptom duration, and the high-resolution computed tomography (HRCT) score were significantly related to the prognosis in the univariate analysis. In the multivariate analysis, the symptom duration remained a significant prognostic factor (hazard ratio of 1-day increase, 1.11; 95% confidence interval, 1.01-1.15; p=0.0427). The area under the receiver operating characteristics curve of symptom duration was statistically significant for survivors versus non-survivors (area under the curve, 0.73; p=0.012). The survival period was significantly shorter

DOI： 10.2169/internalmedicine.9331-17

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives Acute exacerbation of idiopathic pulmonary fibrosis (IPF-AE) has been recognized as a fatal pulmonary disorder, but the exact prognostic factors are unknown. The aim of the present study was to analyze the clinical characteristics of patients with IPF-AE and identify the prognostic factors. Methods The medical records of 59 cases of IPF-AE were retrospectively reviewed. Clinical data, laboratory data, radiographic findings, treatment, and time from the onset of symptoms to the initiation of corticosteroid pulse therapy, i.e. symptom duration, and outcome were analyzed. Results The IPF Stage, Gender-Age-Physiology (GAP) Index, symptom duration, and the high-resolution computed tomography (HRCT) score were significantly related to the prognosis in the univariate analysis. In the multivariate analysis, the symptom duration remained a significant prognostic factor (hazard ratio of 1-day increase, 1.11; 95% confidence interval, 1.01-1.15; p=0.0427). The area under the receiver operating characteristics curve of symptom duration was statistically significant for survivors versus non-survivors (area under the curve, 0.73; p=0.012). The survival period was significantly shorter in the late-treatment groups (≥5 days; n=30) than in the early-treatment groups (<5 days; n=29; log-rank test; p<0.0001). Conclusion The time interval between the onset of symptoms and the initiation of corticosteroid pulse therapy may be an independent prognostic factor in patients with IPF-AE.

DOI： 10.2169/internalmedicine.9331-17

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Cyclic mechanical stretching (CMS) of the alveolar epithelium is thought to contribute to alveolar epithelial injury through an increase in oxidative stress. The aim of this study was to investigate the mechanisms of CMS induced oxidative stress in alveolar epithelial cells (AECs). A549 cells were subjected to CMS, and the levels of 8-isoprostane and 3-nytrotyrosine were measured. Twenty-four hours of CMS induced a significant increase in the levels of 8-isoprostane and 3-nytrotyrosine. Although CMS did not increase the xanthine oxidase activity or the mitochondrial production of reactive oxygen species, it upregulated the expression of nicotine adenine dinucleotide phosphate oxidase (NOX) 2, 4, 5 and DUOX2. The NOX inhibitors DPI and GKT137831 significantly attenuated CMS-induced oxidative stress. Furthermore, the measurement of annexin V/propidium iodide by flow cytometry showed that CMS induced late-phase apoptosis/necrosis, which was also attenuated by both DPI and GKT137831. These data suggest that CMS mainly induces oxidative stress, which may lead to cell injury by activating NOX in AECs.

DOI： 10.1016/j.resp.2017.04.007

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記述言語：英語  

Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that participates in the assembly and turnover of the extracellular matrix, whose expression is regulated by transforming growth factor (TGF)-β1 through activation of mammalian target of rapamycin complex 2 (mTORC2). Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. However, whether XPLN modulates SPARC expression remains unknown. Herein, we investigated the regulatory mechanisms of XPLN in human lung fibroblasts. Effect of XPLN on mTORC2 activity was evaluated by silencing XPLN in human foetal lung fibroblasts (HFL-1 cells), using small interfering RNA. SPARC expression was quantified by quantitative real-time RT-PCR and western blotting. Fibroblasts were treated with TGF-β1, histone deacetylase (HDAC) inhibitors, entinostat, or vorinostat, to assess their effects on XPLN expression. Moreover, the effect of mTORC1 inhibition on SPARC and XPLN was examined. XPLN depletion stimulated SPARC expression and Akt phosphorylation on Ser473. TGF-β1 treatment down-regulated XPLN

DOI： 10.1016/j.pupt.2017.03.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that participates in the assembly and turnover of the extra cellular matrix, whose expression is regulated by transforming growth factor (TGF)-beta 1 through activation of mammalian target of rapamycin complex 2 (mTORC2). Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. However, whether XPLN modulates SPARC expression remains unknown. Herein, we investigated the regulatory mechanisms of XPLN in human lung fibroblasts. Effect of XPLN on mTORC2 activity was evaluated by silencing XPLN in human foetal lung fibroblasts (HFL-1 cells), using small interfering RNA. SPARC expression was quantified by quantitative real-time RT-PCR and western blotting. Fibroblasts were treated with TGF-beta 1, histone deacetylase (HDAC) inhibitors, entinostat, or vorinostat, to assess their effects on XPLN expression. Moreover, the effect of mTORC1 inhibition on SPARC and XPLN was examined. XPLN depletion stimulated SPARC expression and Akt phosphorylation on Ser473. TGF-beta 1 treatment down-regulated XPLN via Smad 2/3. XPLN mRNA expression was up-regulated upon treatment with HDAC inhibitors in a concentration dependent manner, and TGF-beta 1-induced SPARC expression was reversed by entinostat treatment. mTORC1 inhibition by rapamycin and Raptor depletion stimulated SPARC expression. In conclusion, this is the first study describing the involvement of XPLN in the regulation of SPARC. These findings may help uncover the regulatory mechanisms of the mTORC2-SPARC axis. The up-regulation of XPLN by HDAC inhibitors may be a novel therapeutic approach in patients with IPF. (C) 2017 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.pupt.2017.03.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS LTD  

Context: CC chemokine ligand 18 (CCL18) is suggested to play a role in the development of pulmonary fibrosis. Macrophages are thought to be the main source of CCL18, and the effect of pirfenidone, an anti-fibrotic agent for idiopathic pulmonary fibrosis, on the expression of CCL18 in macrophages warrants investigation.Objective: The purpose of this study was to investigate the effect of pirfenidone on the expression of CCL18 in macrophages.Materials and methods: U937 cells were differentiated into macrophages by phorbol myristate acetate and then stimulated with recombinant IL-4 to induce the production of CCL18. The cells were treated with pirfenidone, and the mRNA and protein levels for CCL18 were measured by a reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The effects of pirfenidone on the IL-4 receptor (IL-4R) expression and STAT6 activation were investigated and on the JAK kinase activity were measured using the Z-LYTE kinase assay.Results: Pirfenidone significantly suppressed the expression of CCL18 when the cells were treated with concentrations of 50-250g/mL. Pirfenidone did not affect the expression of the IL-4R components. The selective STAT6 inhibitor AS1517499 suppressed CCL18 expression. Both AS1517499 and pirfenidone suppressed STAT6 phosphorylation (p&lt;.05), although the effect of pirfenidone was less marked than that of AS1517499. The Z-LYTE kinase assay showed a reduction in the activities of JAK1, JAK3 and TYK2 by pirfenidone.Conclusion: Pirfenidone suppresses CCL18 expression in macrophages and this effect is thought to be attributed partly to the inhibition of STAT6 phosphorylation.

DOI： 10.1080/08923973.2016.1247852

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MATTIOLI 1885  

Background and objective: There is growing evidence for anti-inflammatory activities of macrolides in chronic respiratory diseases, such as diffuse panbronchiolitis, cystic fibrosis, or chronic bronchitis. The long-term effect of macrolides in idiopathic pulmonary fibrosis (IPF) is unknown. This study was aimed to investigate the effect of macrolide therapy on the frequency of acute exacerbation (AE) and the mortality in IPF. Methods: A total 52 IPF patients who were treated by combination of conventional agents with or without macrolides were retrospectively reviewed. The primary endpoint was the incidence of AE in IPF patients. We also observed survival rate after the treatment with or without macrolides. Results: AE was observed in 4 of 29 cases (13.8%) treated with macrolides and 8 of 23 cases (34.8%) treated without macrolides, respectively during 36 months. AE free survival rate of macrolide group was significantly better than that of non-macrolide group (logrank p=0.027). Survival rate of IPF patients with macrolide therapy was significantly better than that of patients without macrolide therapy (p=0.047). Conclusion: Our results indicate the potential beneficial efficacy of macrolide therapy combined with oral corticosteroids, immunosuppressive or anti-fibrotic agents in IPF.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS INC  

Combined pulmonary fibrosis and emphysema (CPFE) is an under-recognized syndrome for which the diagnostic use of serum biomarkers is an attractive possibility. We hypothesized that CC16 and/or TGF-beta 1 or combinations with other biomarkers are useful for diagnosing CPFE. Patients with respiratory symptoms and a smoking history, with or without chronic obstructive pulmonary disease, were divided into the following three groups according to findings of high-resolution computed tomography of the chest: controls without either emphysema or fibrosis, patients with emphysema alone, and patients compatible with the diagnosis of CPFE. Serum concentrations of CC16, TGF-beta 1, SP-D, and KL-6 were measured in patients whose condition was stable for at least 3 months. To investigate changes in biomarkers of lung fibrosis in patients with a life-long smoking history, additional measurements were performed on the patients with idiopathic pulmonary fibrosis (IPF) of smoking history. The mean age of the first three groups was 68.0 years, whereas that of the IPF group was 71.8 years, and the groups contained 36, 115, 27, and 10 individuals, respectively. The serum concentration of CC16 in the four groups was 5.67 +/- 0.42, 5.66 +/- 0.35, 9.38 +/- 1.04 and 22.15 +/- 4.64 ng/ml, respectively, indicating that those patients with lung fibrosis had a significantly higher concentration. The combined use of CC16, SP-D, and KL-6 provided supportive diagnosis in conjunction with radiological imaging in diagnosis of CPFE. We conclude that a combination of biomarkers including CC16 could provide useful information to screen and predict the possible diagnosis of CPFE.

DOI： 10.3109/15412555.2014.948994

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MEDICAL ASSOC NIPPON MEDICAL SCH  

We describe a case of pulmonary nocardiosis due to Nocardia asiatica in an immunocompent 64-year-oldfemale.
Wadowsky-Yee-Okuda-alpha-ketoglutarate (WYO alpha) agar, a selective media for Legionella species, was useful for the detection based on the growth-inhibition of normal oral flora and growth-promotion of Nocardia species.

DOI： 10.1272/jnms.82.159

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a high mortality rate. Signalling pathways activated by several tyrosine kinase receptors are known to be involved in lung fibrosis, and this knowledge has led to the development of the triple tyrosine kinase inhibitor nintedanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), for the treatment of IPF. Pulmonary surfactant protein D (SP-D), an important biomarker of IPF, reportedly attenuates bleomycin-induced pulmonary fibrosis in mice. In this study, we investigated whether nintedanib modulates SP-D expression in human lung epithelial (A549) cells using quantitative real-time reverse transcriptase polymerase chain reaction and western blotting. To investigate the mechanisms underlying the effects of nintedanib, we evaluated the phosphorylation of c-Jun N-terminal kinase (JNK) and its downstream target c-Jun. The effect of the JNK inhibitor SP600125 on c-Jun phosphorylation was also tested. Activation of activator protein-1 (AP-1) was examined using an enzyme-linked immunosorbent assay-based test, and cell proliferation assays were performed to estimate the effect of nintedanib on cell proliferation. Furthermore, we treated mice with nintedanib to examine its in vivo effect on SP-D levels in lungs. These experiments showed that nintedanib up-regulated SP-D messenger RNA expression id a dose-dependent manner at concentrations up to 5 mu M, with significant SP-D induction observed at concentrations of 3 mu M and 5 mu M, in comparison with that observed in vehicle controls. Nintedanib stimulated a rapid increase in phosphorylated JNK in A549 cells within 30 min of treatment and stimulated c-Jun phosphorylation, which was inhibited by the JNK inhibitor SP600125. Additionally, nintedanib was found to activate AP-1. A549 cell proliferation was not affected by nintedanib at any of the tested concentrations. Moreover, blocking FGFR, PDGFR, and VEGFR function did not affect nintedanib-induced SP-D expression, suggesting that nintedanib mediates its effects through a mechanism that is distinct from its known role as a tyrosine kinase inhibitor. Nintedanib is also reported to inhibit Src kinase although pre-treatment of cells with a Src kinase inhibitor had no effect on nintedanib-induced SP-D expression. Increased expression of SFTPD mRNA and SP-D protein in the lungs of nintedanib-treated mice was also observed. In this work, we demonstrated that nintedanib up-regulated SP-D expression in A549 cells via the JNK-AP-1 pathway and did not affect cell proliferation. This is the first report describing SP-D induction by nintedanib. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.pupt.2015.03.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Bone marrow-derived fibrocytes reportedly play important roles in the pathogenesis of idiopathic pulmonary fibrosis. Pirfenidone is an anti-fibrotic agent
however, its effects on fibrocytes have not been investigated. The aim of this study was to investigate whether pirfenidone inhibits fibrocyte pool size in the lungs of bleomycin-treated mice.Methods: Bleomycin (100 mg/kg) was infused with osmotic pumps into C57BL/6 mice, and pirfenidone (300 mg/kg/day) was orally administered daily for 2 wk. The lungs were removed, and single-cell suspensions were subjected to fluorescence-activated cell sorter (FACS) analysis to detect fibrocytes, which were defined as CD45 and collagen-I double-positive cells. Immunohistochemistry was performed on the lung specimens to quantify fibrocytes. Chemokines in the lung digests were measured with enzyme-linked immunosorbent assay. The effect of pirfenidone on alveolar macrophages was evaluated with bronchoalveolar lavage (BAL). In a therapeutic setting, pirfenidone administration was initiated 10 days after bleomycin treatment. For chemotaxis assay, lung fibrocytes were isolated with immunomagnetic selection (CD45-positive mesenchymal cells) after culture and allowed to migrate toward chemokines in the presence or absence of pirfenidone. Moreover, the effect of pirfenidone on the expression of chemokine receptors on fibrocytes was evaluated.Results: Pirfenidone significantly ameliorated bleomycin-induced pulmonary fibrosis as assessed with quantitative histology and collagen measurement. Fibrocyte pool size in bleomycin-treated mice lungs was attenuated from 26.5% to 13.7% by pirfenidone on FACS analysis. This outcome was also observed in a therapeutic setting. Immunohistochemistry revealed that fibrocytes were significantly decreased by pirfenidone administration compared with those in bleomycin-treated mice (P = 0.0097). Increased chemokine (CC motif) ligand-2 (CCL2) and CCL12 production in bleomycin-treated mouse lungs was significantly attenuated by pirfenidone (P = 0.0003 and P &lt
0.0001, respectively). Pirfenidone also attenuated macrophage counts stimulated by bleomycin in BAL fluid. Fibrocyte migration toward CCL2 and chemokine (CC motif) receptor-2 expression on fibrocytes was significantly inhibited by pirfenidone in vitro.Conclusions: Pirfenidone attenuated the fibrocyte pool size in bleomycin-treated mouse lungs via attenuation of CCL2 and CCL12 production in vivo, and fibrocyte migration was inhibited by pirfenidone in vitro. Fibrocyte inhibition is considered a mechanism of anti-fibrotic action of pirfenidone. © 2014 Inomata et al.
licensee BioMed Central Ltd.

DOI： 10.1186/1465-9921-15-16

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and objective
Vitamin D supplementation can decrease the vulnerability to pulmonary infections. Therefore, it is speculated that the genes related to vitamin D metabolism are associated with an exacerbation-prone phenotype in chronic obstructive pulmonary disease (COPD). Because genetic variations of group component (GC) affect immunological capacity and serum vitamin D concentration, they could also affect the susceptibility to COPD exacerbation and the disease progression. We investigated the association between GC genetic variations and COPD and its exacerbation frequency in a Japanese population.
Methods
We performed genotype analysis of 361 COPD patients and 219 controls to identify two coding single nucleotide polymorphisms of GC, rs4588 and rs7041. We examined whether these polymorphisms were associated with the frequency of COPD exacerbation and analysed the correlation between the genotypes, COPD, emphysema severity and COPD progression, namely, the annual decline in airflow obstruction and diffusing capacity.
Results
Subjects with a C allele at rs4588 exhibited a higher frequency of exacerbations (P = 0.0048), greater susceptibility to chronic obstructive pulmonary disease (P = 0.0003), and emphysema (P = 0.0029), and a tendency for rapid decline of airflow obstruction (P = 0.0927).
Conclusions
GC variations may affect exacerbation susceptibility, possibly leading to COPD worsening and its progression.

DOI： 10.1111/resp.12277

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Idiopathic interstitial pneumonias such as idiopathic pulmonary fibrosis or fibrotic nonspecific interstitial pneumonia are irreversible progressive pulmonary diseases that often have fatal outcomes. Although the etiology of idiopathic interstitial pneumonias is not yet fully understood, anti-fibrotic and anti-inflammatory agents have shown limited therapeutic effectiveness. Reactive oxygen species and their cytotoxic effects on the lung epithelial cells have been reported to participate in the pathophysiology of the disease. Because superoxide dismutase catalyzes the detoxification of reactive oxygen species, we developed lecithinized superoxide dismutase for the treatment of patients with idiopathic interstitial pneumonias.
Methods: A multicenter, randomized, placebo-controlled trial was conducted as a pilot study to investigate the safety and effectiveness of 40 or 80 mg lecithinized superoxide dismutase in patients with progressive idiopathic interstitial pneumonias who presented with either idiopathic pulmonary fibrosis or corticosteroid-resistant fibrotic nonspecific interstitial pneumonia and showed arterial oxygen tension compatible with stage III or IV on the Japanese severity grading scale for idiopathic interstitial pneumonias. Before and following infusion of lecithinized superoxide dismutase for 28 days, the primary endpoint of forced vital capacity and the secondary endpoints of lactate dehydrogenase, surfactant protein-A, surfactant protein-D and Krebs von den Lungen-6 levels were measured in the serum.
Results: The primary endpoint of forced vital capacity did not improve significantly in the lecithinized superoxide dismutase groups in comparison with the placebo group. The secondary endpoints of lactate dehydrogenase and surfactant protein-A levels were significantly attenuated by 28 days in the higher-dose (80 mg) group. However, these changes returned to the baseline levels by 56 days after the cessation of lecithinized superoxide dismutase. Adverse events and mortality in the drug-treated groups did not differ from those in the placebo group.
Conclusions: Treatment with lecithinized superoxide dismutase is safe and improves the levels of serum markers such as lactate dehydrogenase and surfactant protein-A in patients with advanced idiopathic interstitial pneumonias with severe respiratory dysfunction. Considering the results of the current study, further investigations into the effects and treatment potential of long-term administration of lecithinized superoxide dismutase may be warranted.

DOI： 10.1186/1471-2466-14-86

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Bone marrow-derived fibrocytes reportedly play important roles in the pathogenesis of idiopathic pulmonary fibrosis. Pirfenidone is an anti-fibrotic agent; however, its effects on fibrocytes have not been investigated. The aim of this study was to investigate whether pirfenidone inhibits fibrocyte pool size in the lungs of bleomycin-treated mice.
Methods: Bleomycin (100 mg/kg) was infused with osmotic pumps into C57BL/6 mice, and pirfenidone (300 mg/kg/day) was orally administered daily for 2 wk. The lungs were removed, and single-cell suspensions were subjected to fluorescence-activated cell sorter (FACS) analysis to detect fibrocytes, which were defined as CD45 and collagen-I double-positive cells. Immunohistochemistry was performed on the lung specimens to quantify fibrocytes. Chemokines in the lung digests were measured with enzyme-linked immunosorbent assay. The effect of pirfenidone on alveolar macrophages was evaluated with bronchoalveolar lavage (BAL). In a therapeutic setting, pirfenidone administration was initiated 10 days after bleomycin treatment. For chemotaxis assay, lung fibrocytes were isolated with immunomagnetic selection (CD45-positive mesenchymal cells) after culture and allowed to migrate toward chemokines in the presence or absence of pirfenidone. Moreover, the effect of pirfenidone on the expression of chemokine receptors on fibrocytes was evaluated.
Results: Pirfenidone significantly ameliorated bleomycin-induced pulmonary fibrosis as assessed with quantitative histology and collagen measurement. Fibrocyte pool size in bleomycin-treated mice lungs was attenuated from 26.5% to 13.7% by pirfenidone on FACS analysis. This outcome was also observed in a therapeutic setting. Immunohistochemistry revealed that fibrocytes were significantly decreased by pirfenidone administration compared with those in bleomycin-treated mice (P = 0.0097). Increased chemokine (CC motif) ligand-2 (CCL2) and CCL12 production in bleomycin-treated mouse lungs was significantly attenuated by pirfenidone (P=0.0003 and P &lt; 0.0001, respectively). Pirfenidone also attenuated macrophage counts stimulated by bleomycin in BAL fluid. Fibrocyte migration toward CCL2 and chemokine (CC motif) receptor-2 expression on fibrocytes was significantly inhibited by pirfenidone in vitro.
Conclusions: Pirfenidone attenuated the fibrocyte pool size in bleomycin-treated mouse lungs via attenuation of CCL2 and CCL12 production in vivo, and fibrocyte migration was inhibited by pirfenidone in vitro. Fibrocyte inhibition is considered a mechanism of anti-fibrotic action of pirfenidone.

DOI： 10.1186/1465-9921-15-16

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.prostaglandins.2014.02.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ggi.12031

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記述言語：英語  

DOI： 10.1111/resp.12007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2012.06.081

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Surfactant protein D (SFTPD) induces emphysema in knockout mice, but the association of SFTPD with chronic obstructive pulmonary disease (COPD) and emphysema in humans is unclear. Therefore, we aimed to determine the association between genetic variations in SFTPD and susceptibility to COPD and emphysema. Two populations were studied: population A comprised 270 smokers, including 188 COPD and 82 at-risk subjects, and population B comprised 1131 autopsy cases including 160 cases with emphysema. Six single-nucleotide polymorphisms (SNPs) that tagged the linkage disequilibrium blocks on the entire SFTPD gene were genotyped; the associations of the genotypes with COPD, pulmonary function, percentage of the low-attenuation area (LAA%), and percentage of the airway wall area (WA%) were determined in population A. In population B, the associations of the genotypes with emphysema were assessed. A C allele at SNP rs721917 that results in the replacement of Met with Thr at position 11 in SFTPD was positively correlated with the LAA% in the upper lung (P=1.1x10(-5)) and overall LAA% (P=1.0x10(-4)), and negatively correlated with the serum concentration of SFTPD (P=7x10(-11)) in the population A. The C/C (rs721917/rs10887199) haplotype was associated with emphysema in both the populations. Subjects with a C allele at rs721917 have a lower serum SFTPD concentration and are more susceptible to emphysema. This suggests a protective effect of SFTPD against COPD and emphysema. European Journal of Human Genetics (2012) 20, 230-235; doi:10.1038/ejhg.2011.183; published online 21 September 2011

DOI： 10.1038/ejhg.2011.183

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

We herein report a case of toxic shock syndrome (TSS) associated with the 2009 pandemic H1N1 (pH1N1) influenza virus and a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection in a 16-year-old Vietnamese girl. Staphylococcal enterotoxin B (SEB) was detected in the patient's serum, and the level of anti-SEB antibodies was found to be elevated. A flow cytometric analysis showed evidence of activated SEB-reactive V beta 3(+) and V beta 12(+) T cells. These data suggest that the CA-MRSA-induced activation of SEB-reactive T cells may cause TSS in patients with pH1N1 virus infection. Moreover, this is the first report describing immunological confirmation of SEB contributing directly to TSS in a patient fulfilling the diagnostic criteria of TSS.

DOI： 10.2169/internalmedicine.51.7295

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background/Aim: Recent reports suggest that polymyxin B (PMX)-immobilized fiber may have beneficial effects in idiopathic pulmonary fibrosis (IPF) with acute exacerbation (AE). High mobility group box-1 (HMGB-1) is an important pro-inflammatory mediator that contributes to acute lung inflammation. This study was aimed to investigate whether PMX treatment affects serum HMGB-1 levels and oxygenation in IPF patients with AE. Materials and Methods: Twenty IPF patients with AE were treated by PMX. PMX treatment was carried out once daily for 2 successive days. Serum HMGB-1 levels were measured before and after PMX treatment. We also monitored arterial oxygen tension (PaO(2))/inspiratory oxygen fraction (FiO(2)) (P/F) ratio. PMX fiber columns were analyzed to examine whether HMGB-1 was absorbed by PMX. Results: PMX treatment significantly improved both the serum HMGB-1 level and P/F ratio. HMGB-1 was detected in washing medium from the PMX column. Conclusion: PMX treatment may reduce serum HMGB-1 and improve oxygenation in patients with IPF with AE. Copyright (C) 2011 S. Karger AG, Basel

DOI： 10.1159/000330325

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

Pleiotropic effects of statins have been reported to include inhibition of matrix metalloproteinase (MMP) release from macrophages and endothelial cells. We evaluated whether statins would inhibit MMP release from human lung fibroblasts, which play a major role in remodelling processes.
Monolayer and three-dimensional (3D) collagen gel cultures of fibroblasts were used. Cytokines (tumour necrosis factor-alpha and interleukin-1 alpha) were used to induce MMP release and mRNA expression. Collagen degradation induced by cytokines and neutrophil elastase (NE) was evaluated by quantifying hydroxyproline. Atorvastatin inhibited MMP-1 and -3 release and mRNA expression in both culture systems. Similar results were obtained with simvastatin and fluvastatin.
In 3D cultures where cytokines also stimulated MMP-9 release, atorvastatin also inhibited MMP-9 release. In 3D cultures, cytokines together with NE induced collagen degradation, which was also inhibited by atorvastatin. The effect of atorvastatin was reversed by mevalonate and geranylgeranyl-pyrophosphate but not by farnesyl-pyrophosphate.
The current data suggest that statins may modulate remodelling processes mediated by fibroblasts by inhibiting MMP release.

DOI： 10.1183/09031936.00134707

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DOI： 10.1016/j.yexcr.2010.09.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Background: Excessive production of TGF-beta(1) plays a key role in the tissue remodeling or fibrotic process observed in bronchial asthma, chronic pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). TGF-beta(1) has been reported to decrease the intracellular glutathione level and stimulate the production of reactive oxygen species.Objectives: The aim of this study was to evaluate whether the antioxidant N-acetyl-L-cysteine (NAC) can affect TGF-beta(1)-mediated tissue remodeling in fibroblasts or modulate the production of fibronectin and vascular endothelial growth factor (VEGF) which are believed to be important mediators of tissue repair and remodeling.Methods: To accomplish this, human fetal lung fibroblasts (HFL-1) were used to assess the effect of NAC on the TGF-beta(1)-mediated contraction of floating gels and the TGF-beta(1)-induced mediator production. In addition, the effect of NAC on the TGF-beta(1)-induced differentiation to myofibroblasts was evaluated by assessing alpha-smooth muscle actin (alpha-SMA) expression.Results: NAC significantly abolished the TGF-beta(1)-augmented gel contraction (at 3 mM, gel size 63.4 +/- 2.6% vs. 39.1 +/- 4.1%; p < 0.01) compared with control in a concentration-dependent manner. NAC also significantly inhibited the TGF-beta(1)-augmented fibronectin (p < 0.01) and VEGF (p < 0.01) production in the media of both the three-dimensional gel and monolayer culture. Furthermore, NAC reversed the TGF-beta(1)-stimulated alpha-SMA expression (p < 0.01).Conclusion: These results suggest that NAC can affect the TGF-beta(1)-induced tissue remodeling or fibrotic process in vitro. (c) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.pupt.2009.04.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Togo S, Liu X, Wang X, Sugiura H, Kamio K, Kawasaki S, Kobayashi T, Ertl RF, Ahn Y, Holz O, Magnussen H, Fredriksson K, Skold CM, Rennard SI. PDE4 inhibitors roflumilast and rolipram augment PGE(2) inhibition of TGF-beta 1-stimulated fibroblasts. Am J Physiol Lung Cell Mol Physiol 296: L959-L969, 2009. First published March 20, 2009; doi: 10.1152/ajplung.00508.2007.-Fibrotic diseases are characterized by the accumulation of extracellular matrix together with distortion and disruption of tissue architecture. Phosphodiesterase (PDE)4 inhibitors, by preventing the breakdown of cAMP, can inhibit fibroblast functions and may be able to mitigate tissue remodeling. Transforming growth factor (TGF)-beta 1, a mediator of fibrosis, can potentially modulate cAMP by altering PGE(2) metabolism. The present study assessed whether PDE4 inhibitors functionally antagonize the profibrotic activity of fibroblasts stimulated by TGF-beta 1. The PDE4 inhibitors roflumilast and rolipram both inhibited fibroblast-mediated contraction of three-dimensional collagen gels and fibroblast chemotaxis toward fibronectin in the widely studied human fetal lung fibroblast strain HFL-1 and several strains of fibroblasts from adult human lung. Roflumilast was similar to 10-fold more potent than rolipram. There was a trend for PDE4 inhibitors to inhibit more in the presence of TGF-beta 1 (0.05 &lt; P &lt; 0.08). The effect of the PDE4 inhibitors was mediated through cAMP-stimulated protein kinase A (PKA), although a PKA-independent effect on gel contraction was also observed. The effect of PDE4 inhibitors depended on fibroblast production of PGE(2) and TGF-beta 1-induced PGE(2) production. PDE4 inhibitors together with TGF-beta 1 resulted in augmented PGE(2) production together with increased expression of COX mRNA and protein. The present study supports the concept that PDE4 inhibitors may attenuate fibroblast activities that can lead to fibrosis and that PDE4 inhibitors may be particularly effective in the presence of TGF-beta 1-induced fibroblast stimulation.

DOI： 10.1152/ajplung.00508.2007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Rationale: Fibroblasts are believed to be the major cells responsible for the production and maintenance of extracellular matrix. Alterations in fibroblast functional capacity, therefore, could play a role in the pathogenesis of pulmonary emphysema, which is characterized by inadequate maintenance of tissue structure.
Objectives: To evaluate the hypothesis that deficient fibroblast repair characterizes cells obtained from individuals with chronic obstructive pulmonary disease (COPD) compared with control subjects.
Methods: Fibroblasts were cultured from lung tissue obtained from individuals undergoing thoracotomy and were characterized in vitro.
Measurements and Main Results: Fibroblasts from individuals with COPD, defined by reduced FEV(1), manifested reduced chemotaxis toward fibronectin and reduced contraction of three-dimensional Collagen gels, two bioassays associated with fibroblast repair function. At least two mechanisms appear to account for these differences. Prostaglandin E (PGE), a known inhibitor of fibroblast repair functions, was produced in increased amount by fibroblasts from subjects with COPI), which also expressed increased amounts of the receptors EP2 and EP4, both of which signal through cyclic AMP. Incubation of fibroblasts with indomethacin or with the PKA inhibitor KT-5720 partially restored COPD subject fibroblast function. In addition, fibroblasts from subjects with COPD produced more transforming growth factor (TGF)-beta 1, but manifested reduced response to TGF-beta 1. The functional alterations in fibroblasts correlated with both lung function assessed by FEV(1) and, for the data available, with severity of emphysema assessed by DL(CO).
Conclusions: Fibroblasts from individuals with COPD have reduced capability to sustain tissue repair, which suggests that this may be one mechanism that contributes to the development of emphysema.

DOI： 10.1164/rccm.200706-9290C

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Prostacyclin is a short-lived metabolite of arachidonic acid that is produced by several cells in the lung and prominently by endothelial cells. It increases intracellular cAMP levels activating downstream signaling thus regulating vascular mesenchymal cell functions. The alveolar wall contains a rich capillary network as well as a population of mesenchymal cells, i.e., fibroblasts. The current study evaluated the hypothesis that prostacyclin may mediate signaling between endothelial and mesenchymal cells in the alveolar wall by assessing the ability of prostacyclin analogs to modulate fibroblast release of VEGF. To accomplish this study, human lung fibroblasts were cultured in routine culture on plastic support and in three-dimensional collagen gels with or without three prostacyclin analogs, carbaprostacyclin, iloprost, and beraprost, and the production of VEGF was evaluated by ELISA and quantitative real-time PCR. Iloprost and beraprost significantly stimulated VEGF mRNA levels and protein release in a concentration-dependent manner. These effects were blocked by the adenylate cyclase inhibitor SQ-22536 and by the protein kinase A (PKA) inhibitor KT-5720 and were reproduced by a direct PKA activator but not by an activator of exchange protein directly activated by cAMP (Epac), indicating that cAMP-activated PKA signaling mediated the effect. Since VEGF serves to maintain the pulmonary microvasculature, the current study suggests that prostacyclin is part of a bidirectional signaling network between the mesenchymal and vascular cells of the alveolar wall. Prostacyclin analogs, therefore, have the potential to modulate the maintenance of the pulmonary microcirculation by driving the production of VEGF from lung fibroblasts.

DOI： 10.1152/ajplung.00129.2007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Asthmatic airway remodeling is characterized by goblet cell hyperplasia, angiogenesis, smooth muscle hypertrophy, and subepithelial fibrosis. This study evaluated whether acquired changes in fibroblast phenotype could contribute to this remodeling. Airway and parenchymal fibroblasts from control or chronically ovalbumin (OVA)sensitized and challenged "asthmatic" mice were assessed for several functions related to repair and remodeling +/- exogenous transforming growth factor (TGF)-beta. All OVA-challenged mouse fibroblasts demonstrated augmented gel contraction (P &lt; 0.05) and chemotaxis (P &lt; 0.05); increased TGF-beta(1) (P &lt; 0.05), fibronectin (P &lt; 0.05), and vascular enclothelial growth factor (P &lt; 0.05) release; and expressed more a-smooth muscle actin (P &lt; 0.05). TGF-beta(1) stimulated both control and asthmatic fibroblasts, which retained all differences from control fibroblasts for all features(P &lt; 0.05, all comparisons). Parenchymal fibroblasts proliferated more rapidly (P &lt; 0.05), while airway fibroblasts proliferated similarly compared with control fibroblasts (P = 0.25). Thus, in this animal model, OVA-challenged mouse fibroblasts acquire a distinct phenotype that differs from control fibroblasts. The augmented profibrotic activity and mediator release of asthmatic fibroblasts could contribute to airway remodeling in asthma.

DOI： 10.1165/rcmb.2007-0089OC

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Prostacyclin is an arachidonic acid metabolite that modulates vascular tone within the lung. The current study evaluated the hypothesis that prostacyclin can also modulate tissue remodeling by affecting fibroblast-mediated contraction of extracellular matrix. To accomplish this, fibroblasts were cultured in three-dimensional native type I Collagen gels in the presence of prostacyclin analogs: carbaprostacyclin, iloprost, and beraprost. All three analogs significantly inhibited contraction of the three-dimensional collagen gels mediated by three different fibroblasts. All three analogs significantly inhibited fibronectin release and reduced fibroblast fibronectin mRNA expression. Addition of exogenous fibronectin restored the contractile activity to fibroblasts incubated in the presence of all three analogs. Iloprost and beraprost significantly activated cAMP-dependent protein kinase-A (PKA), and an action through this pathway was confirmed by blockade of the inhibitory effect on contraction and fibronectin release with the PKA inhibitor KT-5720. In contrast, carbaprostacyclin, which is not as selective for the prostacyclin (IP) receptor, did not activate PKA, and its effects on contraction and fibronectin release were not fully blocked by KT-5720. Finally, the CAMP analogs N-6-Benzoyl-(6-Bnz-) cAMP and dibutyryl-cAMP inhibited contraction, and this contrasted with the activity of an Epac selective agonist 8-pCPT-2'-O-Me-cAMP, which had no effect. Taken together, these results indicate that prostacyclin, acting through the IP receptor and by activating PKA, can lead to inhibition of fibronectin release and can subsequently inhibit fibroblast-mediated Collagen gel contraction. The ability of prostacyclin to modulate fibroblast function suggests that prostacyclin can contribute to tissue remodeling.

DOI： 10.1165/rcmb.2007-0009OC

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Prostaglandin E-2 (PGE(2)) has been shown to have a strong cytoprotective effect, inhibiting apoptosis. In the present study, we evaluated whether PGE(2) has a protective effect on cigarette smoke extract (CSE)-induced apoptosis in human lung fibroblasts. Apoptosis was assessed by various methods, including DNA content analysis. CSE (15%-20%) led to apoptosis and induced imbalance in favor of pro- over anti-apoptotic protein expression and activated caspases. PGE(2) blocked CSE-induced apoptosis and modulated the balance of pro- and anti-apoptotic proteins and decreased the activation of caspases. This anti-apoptotic effect was mediated via EP2 receptor activation as the EP2 agonist butaprost mimicked PGE(2) activity and siRNA for the EP2 receptor blocked it. An adenylyl cyclase inhibitor was found to abolish the PGE(2)-mediated cytoprotective effect. Correspondingly, c-AMP analogs blocked CSE-induced apoptosis. Consistently, the protein kinase A (PKA) inhibitor KT-5720 abolished PGE(2)-mediated protection. PGE(2) and butaprost phosphorylated Bad and KT-5720 blocked phosphorylation. These results suggest that PGE(2) inhibits CSE-induced apoptosis via EP2 receptor activation and activation of PKA, which leads to an alteration in the balance between pro- and anti-apoptotic factors. Through such a mechanism, PGE(2) may alter survival of cells in the smoke-exposed lungs, thus affecting the pathogenesis of cigarette smoke-induced disease.

DOI： 10.1002/jcp.20825

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Reactive nitrogen species (RNS) such as peroxynitrite cause cellular injury and tissue inflammation. Excessive production of nitrotyrosine, which is a footprint of RNS, has been observed in the airways of patients with asthma and chronic obstructive pulmonary disease, disorders characterized by tissue remodeling. The aim of this study was to evaluate whether RNS can affect tissue remodeling through direct effects on fibroblasts, and to determine if these effects depend on production of transforming growth factor-beta (TGF-beta). To accomplish this, human fetal lung fibroblasts (HFL-1) were used to assess fibroblast-mediated contraction of floating gels and chemotaxis toward fibronectin. In addition, the ability of fibroblasts to release TGF-beta(1), fibronectin, and vascular endothelial growth factor (VEGF) was assessed by enzyme-linked immunosorbent assay. Authentic peroxynitrite significantly augmented gel contraction (P &lt; 0.01) and chemotaxis (P &lt; 0.01) compared with control in a concentration-dependent manner. Similarly, the peroxynitrite donor 3-morpholynosidenonimine hydrochloride (SIN-1) also augmented gel contraction (P &lt; 0.01). RNS also significantly increased TGF-beta(1) (P &lt; 0.01), fibronectin (P &lt; 0.01), and VEGF (P &lt; 0.01) release into the media in both 3D gel and monolayer culture. Anti-TGF-beta antibody reversed RNS-augmented gel contraction (P &lt; 0.01) and mediator production (P &lt; 0.01). Anti-TGF-beta antibody also partially, but significantly, reversed RNS-augmented chernotaxis toward fibronectin (P &lt; 0.01). Finally, peroxynitrite enhanced expression of alpha(5)beta(1) integrin, which is a receptor for fibronectin (P &lt; 0.01), and neutralizing anti-TGF-beta antibody suppressed peroxynitrite-augmented alpha(5)beta(1) expression (P &lt; 0.01). These results suggest that RNS can affect the tissue repair process by modulating TGF-beta(1).

DOI： 10.1165/rcmb.2005-0339OC

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Transforming growth factor-beta 1 (TGF-beta 1) is a key mediator in tissue repair and fibrosis. Using small interference RNA (siRNA), the role of Smad2 and Smad3 in TGF-beta stimulation of human lung fibroblast contraction of collagenous matrix and induction of alpha-SMA and the role of alpha-SMA in contraction were assessed. HFL-1 cells were transfected with Smad2, Smad3 or control-siRNA, and Cultured in floating Type I collagen gels +/--TGF-beta(1) TGF-beta(1) augmented gel contraction in Srnad2-siRNA- and control-siRNA-treated cells, but had no effect in Smad3-siRNA-treated cells. Similarly, TGF-beta(1), upregulated alpha-SMA in Srnad2-siRNA- and control-siRNA-treated cells, but had no effect on Smad3-siRNA-ti-eated cells. alpha-SMA-siRNA-treated cells did not contact the collagen gels with or without TGF-beta(1), suggesting alpha-SMA is required for gel contraction. Thus, Srnad3 mediates TGF-beta(1)-induced contraction and a-SMA induction in human lung fibroblasts. Smad3, therefore, could be a target for blocking contraction of human fibrotic tissue induced by TGF-beta(1). (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.10.209

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Diffuse panbronchiolitis (DPB) is a chronic inflammatory airway disease predominantly affecting Asian populations. DPB is considered to be a complex genetic disease. Considering the mucous hypersecretion of the disease, we hypothesized that the transcriptional activity of mucin genes may be altered in DPB. We analyzed nucleotide sequences of regulatory region of six mucin genes-MUC1, MUC2, MUC4, MUC5AC, MUC5B, and MUC7-and detected their promoter polymorphisms. Among them, the insertion/deletion polymorphism identified in the MUC5B gene was significantly associated with the disease (p = 0.0001). Transcriptional activity observed in the three major promoter haplotypes corresponded to the strength of the disease association in which these haplotypes are involved. Immunohistochemistry of the lung tissues of DPB revealed that MUC5B was abundantly expressed not only in bronchial glands but also in increased numbers of goblet cells on the bronchial surface, where MUC5AC is predominant and MUC5B expression is generally scarce in the normal lung. Marked mucous hypersecretion observed in DPB may be partly explained by increased and aberrant expression of MUC58. The possible involvement of MUC5B gene in DPB was demonstrated. A further role of the MUC5B polymorphism in its pathogenesis should be studied in the future.

DOI： 10.1164/rccm.200409-1168OC

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Haplotype-based human genome research is important in identifying disease susceptibility genes efficiently. Although haplotype reconstruction by statistical methods is widely used, direct haplotype determination by molecular techniques has also been developed as a complementary method for statistical estimation. In this study, we demonstrate a molecular haplotyping method making use of single-strand conformation polymorphism (SSCP) gels. We identified 10 common SNPs and a dinucleotide insertion/deletion polymorphism within 2-kb region upstream of the transcription initiation site of MUM and determined haplotype structure, dividing the region into two DNA fragments. Real haplotypes were determined unambiguously by our SSCP-based analysis with fragments longer than 1 kb. Haplotypes reconstructed from diploid genotypes in the same region by the statistical methods including EM algorithm were also evaluated. Direct comparison between statistical estimation and direct determination of haplotypes revealed that major haplotypes containing multiple marker sites showing strong LD are estimated in great accuracy but that a variety of haplotypes reflecting weak LD are not reconstructed precisely enough. Our data can be helpful in implementing molecular haplotyping or statistical estimation, since usage of these methods may be determined depending on the haplotype structures. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ygeno.2004.05.008

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記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(株)先端医学社  

内因性のmTORC2 inhibitorであるExchange factor found in platelets, leukemic and neuronal tissues(XPLN)の作用を通じてmTORC2と肺線維化病態との関連を明らかにし、特発性肺線維症(IPF)の新たな治療戦略を模索することを目的とした。肺線維芽細胞として、human fetal lung fibroblast(HFL-1 cell)を使用した。Small interfering RNA(siRNA)を用いてXPLNをノックダウンし、下流に発現する分子への影響をreal-time PCRとwestern blottingを用いて検討した。またsecreted protein acidic and rich in cysteine(SPARC)の蛍光免疫染色も行った。siRNAによるXPLNのノックダウンによりSPARCの発現が増加し、mTORC2とSPARCとの関連が示された。さらに、HDAC inhibitor(HDACi)であるMS275(entinostat)とSAHA(vorinostat)を用いてHFL-1細胞におけるXPLN発現への影響について検討したところ、両HDACiは濃度依存性にHPLNの発現を有意に増加させた。siRaptorによるXPLNの発現増強はmTORC2活性化に伴いそれを抑制しようとする調節機構と考えられた。

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記述言語：日本語   出版者・発行元：(株)先端医学社  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(株)自然科学社  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

DOI： 10.1272/manms.10.209

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.5_561_5

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：日本語   出版者・発行元：(株)自然科学社  

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記述言語：日本語   出版者・発行元：(株)医学書院  

特発性肺線維症の炎症病態への介入が困難な中で、線維化病態に関与するtransforming growth factorやplatelet derived growth factorなどを抑制するピルフェニドンの抗線維化作用に期待が持たれている。二つの国内臨床試験では、肺活量の低下を抑制し、無増悪生存期間を延長し、また、急性増悪を抑制する可能性が示唆されている。抗線維化薬であるピルフェニドンと、現在グローバルな第III相試験が進行中のBIBF1120を中心に概説した。

DOI： 10.11477/mf.1404102321

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記述言語：日本語   掲載種別：書評論文，書評，文献紹介等  

Scopus

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(株)先端医学社  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.1_116_3

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語  

PubMed

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS INC  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(一社)日本結核病学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

DOI： 10.3143/geriatrics.49.119

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.Special_S189_3

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：日本語   出版者・発行元：(株)永井書店  

薬剤性肺障害は、明瞭な薬剤との因果関係が示唆されれば診断可能だが、画像所見や病理所見だけでは最終診断は不可能であり、日常臨床では診断が困難な場合が少なくない。薬剤開発のグローバル化が進む中で、各診療領域において非常に有用な薬剤が使用できるようになってきた反面、薬剤性肺障害のリスクが増大していることも常に認識しなければならない。とくに、特発性肺線維症(IPF)に代表されるようなびまん性肺疾患をベースに発症する場合や、日本人における薬剤性肺障害はより重篤になりやすい特徴があることから、本邦においてびまん性肺疾患を有する症例ではとくに薬剤性肺障害に注意しなければならない。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本呼吸ケア・リハビリテーション学会  

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記述言語：日本語   出版者・発行元：日本気胸・嚢胞性肺疾患学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：克誠堂出版(株)  

症例は60歳代の女性。気管支喘息に対して、プレドニゾロン5mg/日、テオフィリン300mg/日の内服・サルメテロール吸入で加療されていた。気管支喘息発作の重積状態で当院救命救急センター搬送となった。気管内挿管による人工呼吸器管理となり、エピネフリン、ステロイド薬などの投与で速やかに呼吸状態の改善を認めたものの、意識回復後より全盲状態となった。経過中の頭部MRIで後頭葉に高信号域を認め、気管支喘息重積発作に伴う皮質盲と診断した。気管支喘息重積発作に伴うまれな合併症として皮質盲が知られているが、急性期の画像変化を過小評価してしまう可能性があるため注意が必要である。(著者抄録)

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その他リンク： http://search.jamas.or.jp/link/ui/2010307621

記述言語：日本語   出版者・発行元：(一社)日本呼吸ケア・リハビリテーション学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：日本語   出版者・発行元：ライフサイエンス出版(株)  

47歳男性。患者は既往として18歳時に慢性副鼻腔炎の手術、35歳と38歳時に肺炎、40歳時にびまん性汎細気管支炎(DPB)診断を受けた。今回、前医にてDPBに対するクラリスロマイシンの内服治療中であったが、インフルエンザ罹患後に呼吸困難の悪化がみられ、在宅酸素療法(HOT)が導入されるも改善なく、入院となった。しかし、抗生剤の点滴などで改善がみられたものの、HOT中止後に再度の呼吸困難が悪化、HOT再開となり、あわせてアジスロマイシン(AZM)への変更やトブラマイシン吸入が行なわれたが改善せず、著者らの施設へ紹介となった。入院時、寒冷凝集素の高値や低酸素血症、混合性換気障害が認められ、喀痰培養ではMRSA、A. baumannii、P. aeruginosaが検出された。また、X線では両肺過膨張と肺野にびまん性に小粒状陰影、線状網状陰影が確認でき、HRCTではびまん性の小葉中心性粒状陰影、細気管支拡張、気管支壁の肥厚が認められた。以後、エリスロマイシンなどに変更投与されたが改善はみられず、人工呼吸管理による治療も効果なく、患者は診断から7年で死亡となった。

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記述言語：日本語   出版者・発行元：ライフサイエンス出版(株)  

症例1(29歳、兄)。15歳時にびまん性汎細気管支炎(DPB)の診断を受けた。今回、右下肺野にcoarse crackleが聴取され、混合性換気障害を認め、膿性喀痰からムコイド型緑膿菌が検出、汗中Cl濃度は47mmol/Lであった。また、X線では両上肺野優位に浸潤影、気管支拡張像がみられ、CTでは上葉優位に嚢胞状変化を伴う気管支拡張像が認められた。症例2(25歳、弟)。18歳時にDPBの診断を受けた。今回、呼吸音の異常はなかったものの、喀痰からムコイド型緑膿菌が検出され、汗中Cl濃度は40mmol/Lであった。一方、X線では両上肺野優位に浸潤影、気管支拡張像が認められ、CTでは両上中葉・舌区優位に気管支拡張と気管支壁の不整肥厚が確認された。両症例ともDPB以外の副鼻腔気管支症候群の鑑別に各種検査が行なわれたが、いずれも確定診断に至らなかった。しかし、汗中Cl濃度が境界域であったためCFTR遺伝子検索を行なった結果、いずれも一方のアリルでT12201が検出された。

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

呼吸器領域で使用可能な気管支拡張薬には現在、β2刺激薬、抗コリン薬、キサンチン製剤の3種類がある。これらは主に、気管支喘息や慢性閉塞性肺疾患(COPD)の治療に用いられる。短時間作用型β2刺激薬は、気管支喘息では発作治療薬として用いられるが、長時間作用性β2刺激薬(LABA)は長期管理薬として吸入ステロイド薬にadd-onする形で用いられる。COPDではβ2刺激薬に加え、抗コリン薬が可逆性部分であるアセチルコリンによる気流制限を抑制する。2004年より本邦でも長時間作用型抗コリン薬(LAMA)であるチオトロピウムが使用可能になり、COPD患者のQOLは向上している。これらに加えて新規のLABAやLAMAの開発も進められており、さらなる治療効果の改善が期待される。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(株)日本評論社  

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記述言語：日本語   出版者・発行元：(株)南江堂  

気道過分泌がみられるびまん性汎細気管支炎(diffuse panbronchiolitis:DPB)と、ムチン遺伝子群の遺伝子多型との関連を検討した。気道に発現するムチン5B(MUC 5B)遺伝子変異のうち、遺伝子制御領域の2塩基の挿入は疾患群に、欠失は対照群に高頻度に認められた。MUC 5B遺伝子の転写活性を比較した。欠失変異は遺伝子発現を抑制し疾患抵抗性に、挿入変異は発現を増強させ疾患感受性に働く可能性が示唆された。MUC 5Bの気管支、肺での発現を免疫染色にて確認した。DPBではMUC 5Bの異所性発現が認められ、それに伴う気道粘液分泌亢進が病態に重要と推測される。(著者抄録)

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：MOSBY-ELSEVIER  

Web of Science

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

気道過分泌がみられるびまん性汎細気管支炎(diffuse panbronchiolitis;DPB)とmucin遺伝子群の遺伝子多型との関連を検討したところ、気道に発現するmucin5B(MUC5B)遺伝子変異のうち、遺伝子制御領域の2塩基の挿入は疾患群に、欠失は対照群に高頻度に認められた。また、この領域は強い連鎖不平衡にあり、この2塩基の欠失多型を含む代表的なハプロタイプも、DPBと関連を示した。チンパンジーやヨーロッパ系集団ではこれらハプロタイプは認められず、現存する主要なハプロタイプはヒトへの進化後に出現したことが予測された。さらに、遺伝子制御領域に存在するハプロタイプごとに転写活性を解析したところ、欠失変異はMUC5B遺伝子発現を抑制し疾患抵抗性に、挿入変異は発現を増強させ疾患感受性に働く可能性が示唆された。また、MUC5Bの気管支、肺での発現を確認したところ、DPBでは健常気管支と異なり、MUC5Bが気道粘膜表面の広範囲に染色が認められ、気道過分泌と関連しているものと推測された。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)医学書院  

DOI： 10.11477/mf.1404100431

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記述言語：日本語   出版者・発行元：(公財)金原一郎記念医学医療振興財団  

DOI： 10.11477/mf.2425100482

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

ゲノミクス技術を利用して,慢性気道感染症の病態関連分子を抽出し,病態改善に関わるマクロライドの作用点を明確にし,新たな呼吸器疾患治療薬を開発することが期待されている.この点で,ごく最近では,著者らの手によって疾患感受性遺伝子の候補領域である第6染色体のHLAクラスI領域に,ムチン様構造をもつ新規疾患関連遺伝子が同定された.したがって,この分子の粘膜防御における役割を検討することにより,今後はマクロライド剤の有する免疫・炎症の鎮静化機序を,疾患関連遺伝子とその周辺分子との関連で包括的に検討することが可能になると考えられる

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(株)医薬ジャーナル社  

び漫性汎細気管支炎に対する著明な臨床効果が明らかとなっているエリスロマイシン少量長期療法は,気管支拡張症などの気道分泌の亢進をきたす病態にも使用されており,喀痰量の減少など症状の改善がもたらされる.これらより,マクロライド系薬の有する抗菌薬以外の抗炎症作用や気道分泌抑制作用といった側面が注目されている.併用されることの多い去痰薬の中にも杯細胞過形成の抑制や好中球性炎症の抑制により同様の作用を有するものが認められる.これらの薬剤のメカニズムの詳細を明らかにすることは,特定の作用を有する新たな薬剤の開発につながることが期待される

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記述言語：日本語   出版者・発行元：(株)中山書店  

bare lymphocyte syndromeはヒト白血球抗原であるHLAの細胞表面発現が全く,或いは殆どみられないことを特徴とする稀な免疫遺伝性疾患である.特にTAPの欠損に起因して,HLAクラスI分子が細胞表面より失われるタイプでは,小児期に副鼻腔気管支症候群の形で発症し,難治性の皮膚潰瘍を合併することが多い.我が国で報告され,その原因遺伝子変異が同定され,治療法として,び漫性汎細気管支炎同様,マクロライドの有効性が報告された症例を中心に概説した.このように責任分子が特定された希少疾患を詳細に検討することは,今後更に一般的な病態の解明,治療への手がかりとなるものと期待される

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記述言語：日本語   出版者・発行元：克誠堂出版(株)  

び漫性汎細気管支炎の病因に関しては様々な議論が行われてきたが,人種特異性から遺伝素因があるとの観点で行われたHLAの調査はB54と高い相関を示した.ヒトゲノム計画という世界的な流れの中で,マイクロサテライトや一塩基多型等の遺伝マーカーを用いた多因子疾患の感受性遺伝子の同定が盛んに試みられているが,び漫性汎細気管支炎でもこの流れを受け,HLA領域を含めた多因子疾患としての病像を捉えようとする試みが行われている

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その他リンク： http://search.jamas.or.jp/link/ui/2003009840

記述言語：日本語   出版者・発行元：(株)日本小児医事出版社  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(株)先端医学社  

び漫性汎細気管支炎(DPB)発症の遺伝的背景の存在を示唆するものとして,地域や同一家系内集積性,特定のHLA抗原の保有などがあげられる.マイクロサテライトマーカー等の遺伝マーカーを用いたアプローチにより,DPB感受性遺伝子がHLA-B〜A座間の約200kbの領域に存在する可能性が推定されている

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記述言語：日本語   出版者・発行元：克誠堂出版(株)  

多くの疾患は,いくつかの遺伝子の軽微な違い(多型)の組み合わせと,環境要因,外的要因の絡み合いによって発症する多因子疾患と考えられる.び漫性汎細気管支炎は,東アジア人の遺伝要因が発症に重要な役割を果たしていると考えられており,特にHLAとの関連から疾患感受性遺伝子の探求が行われてきた.ヒトゲノム計画とそれに伴う疾患感受性遺伝子探索という昨今の流れの中で,これ迄の研究を振り返り,今後の方向性について言及した

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：ライフサイエンス出版(株)  

16歳女.咳嗽,喀痰,全身倦怠感を主訴とした.気管支拡張症の診断でerythromycin,clarithromycinを服用していた.び漫性汎細気管支炎(DPB)と診断したが,前医でマクロライドを投与されており,他疾患の可能性も考慮に入れ精査を行った.cystic fibrosis transmembrane conductance regulator(CFTR)遺伝子の検索で一方のアリル上の変異が認められた.この変異と正常のCFTR遺伝子をヘテロに有していた

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：福島医学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.22.3_214_3

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

CiNii Books

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

化学療法後23例中2例,外科療法後14例中2例,放射線療法後8例中2例にIIPの急性増悪が認められた.治療前の血清CRP値が,急性増悪群は5.12±2.27mg/dl,非増悪群は2.26±2.29mg/dlで急性増悪群が有意に高値であった.一方,ESR,LDH,WBC,PaO2,%VCには有意差は認められなかった.組織学的評価で,急性増悪例と非増悪例に明らかな差は認められなかったが,急性増悪例に組織学的に活動性と思われる症例が存在した.急性増悪した6例中5例は3ヵ月以内に死亡した.IIP合併肺癌症例の肺癌治療は,新しいマーカーや経気管支肺生検などを用い,IIPの活動性のより正確な評価の上に行うべきと考えられた

DOI： 10.2482/haigan.39.955

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER LUNG ASSOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER LUNG ASSOC  

Web of Science

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

CiNii Books

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：ライフサイエンス出版(株)  

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記述言語：日本語   出版者・発行元：日本肺癌学会  

CiNii Books

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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会議種別：口頭発表（招待・特別）  

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